Patients with non-small-cell lung cancer respond best to salvage chemotherapy when pre-treated with PD-1/PD-L1 inhibitors

Patients with advanced non-small-cell lung cancer (NSCLC) who require salvage chemotherapy are 30% more likely to achieve a partial response if they have been pre-treated with a PD-1/PD-L1 checkpoint inhibitor compared to those who have not, according to a study presented at the European Lung Cancer Conference (ELCC) 2017 in Geneva, Switzerland 1.

The preliminary findings could potentially open the door to a new way of sequencing cancer therapy, as reported by the study authors.

“Our results are of utmost importance for NSCLC patients,” said lead investigator Sacha Rothschild, MD, PhD, from University Hospital Basel, Department of Medicine, Division of Oncology, Switzerland.

“Checkpoint inhibitors are currently the standard of care for NSCLC patients in the 2nd-line setting after chemotherapy and are used for a subset of patients with high PD-L1 expression as front-line therapy. So far, it is unclear how to treat patients not responding to immune checkpoint inhibitors or progressing after initial response to these agents. The activity of conventional chemotherapy in this setting has not been investigated so far. Therefore, these results are good news for patients that progress after immunotherapy and are still fit enough to receive further palliative therapy.”

The retrospective analysis included 82 patients with stage IV NSCLC, including adenocarcinoma (n=63), squamous cell carcinoma (n=18), and one case of large cell carcinoma.

A total of 67 patients had been previously treated with a PD-1/PD-L1 inhibitors (cases) including 56 patients who received nivolumab, seven who had received pembrolizumab, and four who had received atezolizumab.

The other 15 patients who had not been treated with PD-1/PD-L1 inhibitors served as controls.

All patients had been pre-treated with chemotherapy, with a mean of 2.37 prior regimens among cases and 1.93 in controls.

Computed tomography (CT) scans performed within the first month and then every six weeks showed a significantly higher partial response rate in cases compared to controls (27% vs 7%, odds ratio [OR] 0.3, P<0.0001).

Stable disease was seen in 51% of cases and 53% of controls, and progressive disease was seen in 22% of cases versus 40% of controls.

Multiple logistic regression showed that age, gender, number of prior chemotherapy regimens, tumour histology, smoking status, or different salvage chemotherapy regimens were not independently associated with the likelihood of achieving partial response.

“At this point we can only speculate on the reasons for better response in those pre-treated with checkpoint inhibitors,” said Rothschild. “Probably the activation of the immune system by checkpoint inhibition might render tumour cells more sensitive to chemotherapy. Or chemotherapy may help the tumour-specific T-cells to enter the tumour microenvironment and to exert their function.”

Rothschild said investigations are ongoing into the duration of response and toxicity, and he cautioned that this finding must be further explored in larger and prospective cohorts.

Commenting on the study, Marina Garassino, MD, Head of Thoracic Medical Oncology, National Cancer Institute of Milan (Fondazione IRCCS Istituto Nazionale dei Tumori) was enthusiastic about the potential implications.

“This is the first research suggesting that chemotherapy could potentially work better after immunotherapy,” she said. “All of us treating patients with immunotherapy have had a feeling about this because we’ve seen unexpected results with some patients, but this is the first study in which this phenomenon is formally described. Although the results are very preliminary, they suggest that immunotherapy can change the natural history of the disease and the micro-environment of the tumour, therefore rendering it more sensitive to chemotherapy. This could potentially point to new areas of research and new sequences of treatment.”

1 Abstract 91PD – ‘Response to salvage chemotherapy following exposure to PD-1/PD-L1 inhibitors in patients with NSCLC’ will be presented by Dr Sacha Rothschild during the Poster Discussion session ‘Targeted therapies and immunotherapies’ on Sunday 7 May, 14:45 CEST.